KEGG   PATHWAY: hsa04935
hsa04935                    Pathway                                
Growth hormone synthesis, secretion and action - Homo sapiens (human)
Growth hormone (GH) is a peptide hormone secreted from the anterior pituitary and plays a critical role in cell growth, development, and metabolism throughout the body. GH secretion occurs episodically and is primarily under the control of two hypothalamic neuroendocrine hormones: GH-releasing hormone (GHRH), which stimulates GH secretion, and somatostatin, which inhibits GH secretion. GHRH interacts with a G protein-coupled receptor (GHRHR) in somatotroph cells to activate the cAMP signaling pathway, which leads to increased GH mRNA transcription and release. Once released into the circulation, GH binds to cell-surface GHR in target tissues such as liver, muscle, bone, and adipose tissue. Binding leads to activation of JAK2 that in turn triggers an array of signaling cascade including Raf-MEK-ERK, PI3K-Akt, and STAT5. ERK, Akt, and STAT5 all promote growth via the synthesis and secretion of IGF-1.
Organismal Systems; Endocrine system
Pathway map
hsa04935  Growth hormone synthesis, secretion and action

nt06324  GHRH-GH-IGF signaling
N00907  GH-Jak-STAT signaling pathway
N00910  GHRHR-PKA-GH signaling pathway
D11651  Edotreotide gallium Ga-68
D11882  Copper Cu 64 dotatate
Homo sapiens (human) [GN:hsa]
2691  GHRH; growth hormone releasing hormone [KO:K05260]
2692  GHRHR; growth hormone releasing hormone receptor [KO:K04584]
2778  GNAS; GNAS complex locus [KO:K04632]
107  ADCY1; adenylate cyclase 1 [KO:K08041] [EC:]
108  ADCY2; adenylate cyclase 2 [KO:K08042] [EC:]
109  ADCY3; adenylate cyclase 3 [KO:K08043] [EC:]
196883  ADCY4; adenylate cyclase 4 [KO:K08044] [EC:]
111  ADCY5; adenylate cyclase 5 [KO:K08045] [EC:]
112  ADCY6; adenylate cyclase 6 [KO:K08046] [EC:]
113  ADCY7; adenylate cyclase 7 [KO:K08047] [EC:]
114  ADCY8; adenylate cyclase 8 [KO:K08048] [EC:]
115  ADCY9; adenylate cyclase 9 [KO:K08049] [EC:]
55811  ADCY10; adenylate cyclase 10 [KO:K11265] [EC:]
6750  SST; somatostatin [KO:K05237]
6751  SSTR1; somatostatin receptor 1 [KO:K04217]
6752  SSTR2; somatostatin receptor 2 [KO:K04218]
6753  SSTR3; somatostatin receptor 3 [KO:K04219]
6755  SSTR5; somatostatin receptor 5 [KO:K04221]
2770  GNAI1; G protein subunit alpha i1 [KO:K04630]
2773  GNAI3; G protein subunit alpha i3 [KO:K04630]
2771  GNAI2; G protein subunit alpha i2 [KO:K04630]
5566  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:]
5567  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:]
5568  PRKACG; protein kinase cAMP-activated catalytic subunit gamma [KO:K04345] [EC:]
1385  CREB1; cAMP responsive element binding protein 1 [KO:K05870]
1386  ATF2; activating transcription factor 2 [KO:K04450]
468  ATF4; activating transcription factor 4 [KO:K04374]
10488  CREB3; cAMP responsive element binding protein 3 [KO:K09048]
90993  CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048]
64764  CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048]
84699  CREB3L3; cAMP responsive element binding protein 3 like 3 [KO:K09048]
148327  CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048]
9586  CREB5; cAMP responsive element binding protein 5 [KO:K09047]
1388  ATF6B; activating transcription factor 6 beta [KO:K09049]
1387  CREBBP; CREB binding protein [KO:K04498] [EC:]
2033  EP300; E1A binding protein p300 [KO:K04498] [EC:]
5449  POU1F1; POU class 1 homeobox 1 [KO:K09363]
2353  FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]
2688  GH1; growth hormone 1 [KO:K05438]
2689  GH2; growth hormone 2 [KO:K05438]
1442  CSH1; chorionic somatomammotropin hormone 1 [KO:K05438]
1443  CSH2; chorionic somatomammotropin hormone 2 [KO:K05438]
51738  GHRL; ghrelin and obestatin prepropeptide [KO:K05254]
2693  GHSR; growth hormone secretagogue receptor [KO:K04284]
2776  GNAQ; G protein subunit alpha q [KO:K04634]
2767  GNA11; G protein subunit alpha 11 [KO:K04635]
23236  PLCB1; phospholipase C beta 1 [KO:K05858] [EC:]
5330  PLCB2; phospholipase C beta 2 [KO:K05858] [EC:]
5331  PLCB3; phospholipase C beta 3 [KO:K05858] [EC:]
5332  PLCB4; phospholipase C beta 4 [KO:K05858] [EC:]
5578  PRKCA; protein kinase C alpha [KO:K02677] [EC:]
5579  PRKCB; protein kinase C beta [KO:K19662] [EC:]
5582  PRKCG; protein kinase C gamma [KO:K19663] [EC:]
3708  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
3709  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
3710  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
779  CACNA1S; calcium voltage-gated channel subunit alpha1 S [KO:K04857]
775  CACNA1C; calcium voltage-gated channel subunit alpha1 C [KO:K04850]
776  CACNA1D; calcium voltage-gated channel subunit alpha1 D [KO:K04851]
778  CACNA1F; calcium voltage-gated channel subunit alpha1 F [KO:K04853]
2690  GHR; growth hormone receptor [KO:K05080]
3717  JAK2; Janus kinase 2 [KO:K04447] [EC:]
5335  PLCG1; phospholipase C gamma 1 [KO:K01116] [EC:]
5336  PLCG2; phospholipase C gamma 2 [KO:K05859] [EC:]
6464  SHC1; SHC adaptor protein 1 [KO:K06279]
25759  SHC2; SHC adaptor protein 2 [KO:K17447]
53358  SHC3; SHC adaptor protein 3 [KO:K17448]
399694  SHC4; SHC adaptor protein 4 [KO:K17449]
2885  GRB2; growth factor receptor bound protein 2 [KO:K04364]
6654  SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
6655  SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
3265  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
3845  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
4893  NRAS; NRAS proto-oncogene, GTPase [KO:K07828]
5894  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:]
5604  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
5605  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
6772  STAT1; signal transducer and activator of transcription 1 [KO:K11220]
6774  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
6776  STAT5A; signal transducer and activator of transcription 5A [KO:K11223]
6777  STAT5B; signal transducer and activator of transcription 5B [KO:K11224]
3667  IRS1; insulin receptor substrate 1 [KO:K16172]
8660  IRS2; insulin receptor substrate 2 [KO:K07187]
8471  IRS4; insulin receptor substrate 4 [KO:K17446]
5295  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
5296  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
8503  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
5290  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:]
5293  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:]
5291  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:]
207  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:]
208  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:]
10000  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:]
2475  MTOR; mechanistic target of rapamycin kinase [KO:K07203] [EC:]
2932  GSK3B; glycogen synthase kinase 3 beta [KO:K03083] [EC:]
3479  IGF1; insulin like growth factor 1 [KO:K05459]
3726  JUNB; JunB proto-oncogene, AP-1 transcription factor subunit [KO:K09028]
8651  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
8835  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
9021  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
3483  IGFALS; insulin like growth factor binding protein acid labile subunit [KO:K17256]
3486  IGFBP3; insulin like growth factor binding protein 3 [KO:K10138]
5747  PTK2; protein tyrosine kinase 2 [KO:K05725] [EC:]
9564  BCAR1; BCAR1 scaffold protein, Cas family member [KO:K05726]
1398  CRK; CRK proto-oncogene, adaptor protein [KO:K04438]
1399  CRKL; CRK like proto-oncogene, adaptor protein [KO:K04438]
4214  MAP3K1; mitogen-activated protein kinase kinase kinase 1 [KO:K04416] [EC:]
5606  MAP2K3; mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:]
6416  MAP2K4; mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:]
5608  MAP2K6; mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:]
5599  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:]
5602  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:]
5601  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:]
5600  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:]
6300  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:]
5603  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:]
1432  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:]
C00076  Calcium cation
C00165  Diacylglycerol
C00575  3',5'-Cyclic AMP
C01245  D-myo-Inositol 1,4,5-trisphosphate
Nishad R, Mukhi D, Menon R K, Pasupulati A.
Growth Hormone and Metabolic Homeostasis
Eur Med J 6:78-87 (2018)
Lu M, Flanagan JU, Langley RJ, Hay MP, Perry JK
Targeting growth hormone function: strategies and therapeutic applications.
Signal Transduct Target Ther 4:3 (2019)
Argetsinger LS, Carter-Su C
Mechanism of signaling by growth hormone receptor.
Physiol Rev 76:1089-107 (1996)
Carter-Su C, Schwartz J, Smit LS
Molecular mechanism of growth hormone action.
Annu Rev Physiol 58:187-207 (1996)
Carter-Su C, Rui L, Herrington J
Role of the tyrosine kinase JAK2 in signal transduction by growth hormone.
Pediatr Nephrol 14:550-7 (2000)
Dehkhoda F, Lee CMM, Medina J, Brooks AJ
The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects.
Front Endocrinol (Lausanne) 9:35 (2018)
Carter-Su C, Schwartz J, Argetsinger LS
Growth hormone signaling pathways.
Growth Horm IGF Res 28:11-5 (2016)
Berryman DE, Henry B, Hjortebjerg R, List EO, Kopchick JJ
Developments in our understanding of the effects of growth hormone on white adipose tissue from mice: implications to the clinic.
Expert Rev Endocrinol Metab 11:197-207 (2016)
Zhu T, Goh EL, LeRoith D, Lobie PE
Growth hormone stimulates the formation of a multiprotein signaling complex involving p130(Cas) and CrkII. Resultant activation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK).
J Biol Chem 273:33864-75 (1998)
Choi S (ed).
Encyclopedia of Signaling Molecules
Springer International Publishing
Gracia-Navarro F, Castano JP, Malagon MM, Sanchez-Hormigo A, Luque RM, Hickey GJ, Peinado JR, Delgado E, Martinez-Fuentes AJ
Research progress in the stimulatory inputs regulating growth hormone (GH) secretion.
Comp Biochem Physiol B Biochem Mol Biol 132:141-50 (2002)
Bertherat J
Nuclear effects of the cAMP pathway activation in somatotrophs.
Horm Res 47:245-50 (1997)
Tuggle CK, Trenkle A
Control of growth hormone synthesis.
Domest Anim Endocrinol 13:1-33 (1996)
Cohen LE, Hashimoto Y, Zanger K, Wondisford F, Radovick S
CREB-independent regulation by CBP is a novel mechanism of human growth hormone gene expression.
J Clin Invest 104:1123-30 (1999)
Khatib N, Gaidhane S, Gaidhane AM, Khatib M, Simkhada P, Gode D, Zahiruddin QS
Ghrelin: ghrelin as a regulatory Peptide in growth hormone secretion.
J Clin Diagn Res 8:MC13-7 (2014)
Lengyel AM
From growth hormone-releasing peptides to ghrelin: discovery of new modulators of GH secretion.
Arq Bras Endocrinol Metabol 50:17-24 (2006)
Anderson LL, Jeftinija S, Scanes CG, Stromer MH, Lee JS, Jeftinija K, Glavaski-Joksimovic A
Physiology of ghrelin and related peptides.
Domest Anim Endocrinol 29:111-44 (2005)
Camina JP, Carreira MC, Micic D, Pombo M, Kelestimur F, Dieguez C, Casanueva FF
Regulation of ghrelin secretion and action.
Endocrine 22:5-12 (2003)
Yang SK, Steyn F, Chen C
Influence of membrane ion channel in pituitary somatotrophs by hypothalamic regulators.
Cell Calcium 51:231-9 (2012)
Melmed S
Acromegaly pathogenesis and treatment.
J Clin Invest 119:3189-202 (2009)
hsa04010  MAPK signaling pathway
hsa04020  Calcium signaling pathway
hsa04024  cAMP signaling pathway
hsa04630  JAK-STAT signaling pathway
KO pathway

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